OVERVIEW. Abnormalities of nicotinic acetylcholine system in schizophrenia are implied by the high prevalence of cigarette smoking. Because animal and human studies have shown that nicotinic acetylcholine receptors (nAChRs) play an important role in cognitive function, cognitive deficits in schizophrenia also suggest abnormalities in these receptors. Postmortem studies showed abnormalities in high affinity nAChRs in these patients but the direction of the abnormalities (increase or decrease) were not consistent probably because it is difficult to control the effects of cigarette smoking and neuroleptics in such studies. In vivo imaging studies of these receptors have been needed where these factors are well controlled. In addition, imaging studies are necessary to study relationship between nAChRs and psychiatric symptoms including cognitive impairments. We plan to use a new single photon emission computed tomography (SPECT) tracer, [I-123]5-I-A-85380, which appears suitable for imaging the high affinity alpha4beta2 subtype of nAChRs. We plan to compare four groups, 1) schizophrenia smokers, 2) schizophrenia non-smokers, 3) healthy smokers, and 4) healthy non-smokers. All patients will be on stable doses of olanzapine or risperidone. In addition to comparing [I-123]5-I-A-85380 binding among these groups, relationship will be studied between psychiatric symptoms or cognitive dysfunction and the SPECT measurement of the receptors. Further, to study the reliability of the SPECT measurement, a test retest study will be performed in healthy subjects with a wide age range. The proposed study will explore the roles of nAChRs in the psychiatric symptoms, particularly the cognitive deficits in schizophrenia, which is the central impairment of this disorder. New findings in this research will lead to enhanced treatment of the cognitive deficits. WORK OVER PAST YEAR. 1) We have measured the distribution of this tracer in human subjects to calculate the resulting radiation exposure to organs of the body (Fujita et al., 2002). These results have shown that the doses of the radiotracer can be safely administered to human subjects. 2) We have developed improved methods for quantitation of the resulting image (Ichise et al., in press). 3) We have evaluated new methods to correct for scatter in the SPECT images and have more accurate quantitation (Vines et al., submitted). 4) We have established a laboratory at NIMH for the production of the radiotracer. 5) A protocol for the use if this tracer in patients with schizophrenia (described above) has been submitted to the IRB and is approved, pending approval by the FDA.